Among men, low testosterone levels may to more severe disease, found a Washington University study, reports MedicalBrief.
Although the study could not prove low testosterone as a cause of severe COVID-19, and researchers said low levels could simply serve as a marker of some other causal factors, they urged caution with ongoing clinical trials investigating hormonal therapies that block or lower testosterone or increase oestrogen as a treatment for men with COVID-19.
The study contradicts widespread assumptions that higher testosterone may explain why men, on average, develop more severe COVID-19 than women do.
“During the pandemic, there has been a prevailing notion that testosterone is bad,” said senior author and cardiologist Prof Abhinav Diwan. “But we found the opposite in men. If a man had low testosterone when he first came to the hospital, his risk of having severe COVID-19, meaning his risk of requiring intensive care or dying, was much higher compared with men who had more circulating testosterone. And if testosterone levels dropped further during hospitalisation, the risk increased.”
The researchers measured several hormones in blood samples from 90 men and 62 women who went to Barnes-Jewish Hospital with COVID-19 symptoms and who had confirmed cases of the illness. For the 143 patients admitted to the hospital, researchers measured hormone levels again at days 3, 7, 14 and 28, as long as the patients remained hospitalised over these time frames. They also measured levels of oestradiol, a form of oestrogen produced by the body, and IGF-1, an important growth hormone similar to insulin and which helps maintain muscle mass.
No link was found between levels of any hormone and disease severity among women. Among men, only testosterone levels were linked to COVID-19 severity. A blood testosterone level of 250 nanograms per decilitre or less is considered low in adult men. At hospital admission, men with severe COVID-19 had average testosterone levels of 53 nanograms per decilitre; men with less severe disease had average levels of 151 nanograms per decilitre. By day three, the average testosterone level of the most severely ill men was only 19 nanograms per decilitre.
The lower the testosterone levels, the more severe the disease: for example, those with the lowest levels of testosterone were most at risk of going on a ventilator, needing intensive care, or dying.
Over the course of the study, 37 patients died (25 of whom were men).
Other factors known to increase the risk of severe COVID-19, including advanced age, obesity and diabetes, are associated with lower testosterone, said the researchers. "The groups of men getting sicker were known to have lower testosterone across the board," said first author Dr Sandeep Dhindsa, an endocrinologist at Saint Louis University. "We also found that those men with COVID-19 who were not severely ill initially, but had low testosterone levels, were likely to need intensive care or intubation over the next two or three days. Lower testosterone levels seemed to predict which patients were likely to become very ill over the next few days."
Additionally, it was found that lower testosterone levels also correlated with higher levels of inflammation and an increase in the activation of genes allowing the body to carry out the functions of circulating sex hormones inside the cells. In other words, the body may be adapting to less testosterone circulating in the bloodstream by escalating its ability to detect and use the hormone. The researchers don't yet know the implications of this adaptation and are calling for more research.
“We are now investigating a possible association between sex hormones and cardiovascular outcomes in long COVID-19, when the symptoms linger over many months,” said Diwan. “We also are interested in whether men recovering from COVID-19, including those with long COVID-19, may benefit from testosterone therapy: this has been used on men with low sex hormone levels, so it may be worth investigating whether a similar approach can help male COVID-19 survivors with rehabilitation.”
Association of Circulating Sex Hormones With Inflammation and Disease Severity in Patients With COVID-19
Authors: Sandeep Dhindsa, Nan Zhang, Michael J. McPhaul, Zengru Wu, Amit K. Ghoshal, Emma C. Erlich, Kartik Mani, Gwendalyn J. Randolph, John R. Edwards, Philip A. Mudd, Abhinav Diwan.
Published on25 May in JAMA Network Open
Question Are circulating sex hormones associated with disease severity in patients with COVID-19?
Findings In a cohort study of 152 patients with COVID-19, including 143 patients who were hospitalized, testosterone concentrations at presentation and on day 3 were inversely associated with disease severity and circulating inflammatory cytokine concentrations in men but not in women. Transcriptional profiling of circulating mononuclear cells revealed upregulation of hormone signaling pathways in patients requiring intensive care vs those with milder disease.
Meaning These findings suggest that low testosterone concentrations may play a mechanistic role in worse outcomes observed in men with COVID-19, underscoring the need for clinical trials to test this hypothesis.
Importance Male sex is a risk factor for developing severe COVID-19 illness. It is not known whether sex hormones contribute to this predisposition.
Objective To investigate the association of concentrations of serum testosterone, estradiol, and insulinlike growth factor 1 (IGF-1, concentrations of which are regulated by sex hormone signaling) with COVID-19 severity.
Design, Setting, and Participants This prospective cohort study was conducted using serum samples collected from consecutive patients who presented from March through May 2020 to the Barnes Jewish Hospital in St Louis, Missouri, with COVID-19 (diagnosed using nasopharyngeal swabs).
Exposures Testosterone, estradiol, and IGF-1 concentrations were measured at the time of presentation (ie, day 0) and at days 3, 7, 14, and 28 after admission (if the patient remained hospitalized).
Main Outcomes and Measures Baseline hormone concentrations were compared among patients who had severe COVID-19 vs those with milder COVID-19 illness. RNA sequencing was performed on circulating mononuclear cells to understand the mechanistic association of altered circulating hormone concentrations with cellular signaling pathways.
Results Among 152 patients (90 [59.2%] men; 62 [40.8%] women; mean [SD] age, 63  years), 143 patients (94.1%) were hospitalized. Among 66 men with severe COVID-19, median [interquartile range] testosterone concentrations were lower at day 0 (53 [18 to 114] ng/dL vs 151 [95 to 217] ng/dL; P = .01) and day 3 (19 [6 to 68] ng/dL vs 111 [49 to 274] ng/dL; P = .006) compared with 24 men with milder disease. Testosterone concentrations were inversely associated with concentrations of interleukin 6 (β = −0.43; 95% CI, −0.52 to −0.17; P < .001), C-reactive protein (β = −0.38; 95% CI, −0.78 to −0.16; P = .004), interleukin 1 receptor antagonist (β = −0.29; 95% CI, −0.64 to −0.06; P = .02), hepatocyte growth factor (β = −0.46; 95% CI, −0.69 to −0.25; P < .001), and interferon γ–inducible protein 10 (β = −0.32; 95% CI, −0.62 to −0.10; P = .007). Estradiol and IGF-1 concentrations were not associated with COVID-19 severity in men. Testosterone, estradiol, and IGF-1 concentrations were similar in women with and without severe COVID-19. Gene set enrichment analysis revealed upregulated hormone signaling pathways in CD14+CD16− (ie, classical) monocytes and CD14−CD16+ (ie, nonclassical) monocytes in male patients with COVID-19 who needed intensive care unit treatment vs those who did not.
Conclusions and Relevance In this single-center cohort study of patients with COVID-19, lower testosterone concentrations during hospitalization were associated with increased disease severity and inflammation in men. Hormone signaling pathways in monocytes did not parallel serum hormone concentrations, and further investigation is required to understand their pathophysiologic association with COVID-19.
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